Each year more than 1,400,000 men and women in the United States (U.S.) experience an acute coronary event. Most of these coronary events, including coronary death, result from plaque rupture and thrombosis on non-critical coronary stenoses. However, mechanisms responsible for conversion of chronic coronary atherosclerosis to acute coronary events are not well understood. Lower extremity peripheral arterial disease (PAD) affects 8 million men and women in the U.S. Compared to those without PAD, men and women with PAD have an increased rate of coronary events. Our preliminary data from annually measured biomarkers in persons with PAD demonstrate that elevated levels of annually measured C-reactive protein (CRP), serum amyloid A (SAA), and D-dimer are more closely associated with near-term cardiovascular or all-cause mortality than later-term (remote) cardiovascular or all- cause mortality. Our preliminary data also demonstrate that greater annual increases in these biomarkers are associated with higher rates of cardiovascular mortality during the year after the increase. Based on our preliminary data, we hypothesize that among persons with PAD, biomarker levels are higher during time periods immediately preceding an acute coronary event compared to time periods not immediately preceding a coronary event. While our preliminary data from annually measured biomarkers in persons with PAD support this hypothesis, this phenomenon has not been definitively demonstrated. Our aims will be tested in a cohort of 650 participants with PAD, followed prospectively for two years. Biomarkers we will study are CRP, SAA, and D-dimer. Biomarkers will be measured at baseline and every two months during follow-up. The primary aims of this study are as follows. Specific Aim #1. Among participants with PAD who experience an acute coronary event during follow-up, we will determine whether biomarker levels measured immediately prior to the coronary event are higher than levels that do not immediately precede coronary events. Specific Aim #2, Part 1. We will determine whether participants who experience a coronary event (cases) have higher biomarker levels at the visit immediately prior to the event than participants who have not experienced a coronary event (controls) at the time of the case event. Specific Aim #2, Part 2. We will determine whether participants who experience a coronary event (cases) have a greater increase in biomarkers during the time period leading up to the event compared to participants who have not experienced a coronary event (controls). Results of this study are expected to provide important information about the pathophysiology of acute coronary events. This information is expected to lead to improved therapies, in subsequent studies, for prevention and treatment of acute coronary events. PUBLIC HEALTH RELEVANCE: In the United States, more than 1,400,000 men and women suffer a heart attack or other similar coronary event each year. Mechanisms responsible for converting chronic, stable coronary atherosclerosis to an acute coronary event are not well understood. The purpose of this study is to determine whether levels of specific circulating biomarkers rapidly increase during the weeks immediately preceding coronary events in persons who are at high risk for coronary events. Findings may help clinicians identify patients who are at particularly high-risk for an impending heart attack. Results are also expected to elucidate specific triggers of acute coronary events.